Mutational characteristics and clinical outcomes for lung adenocarcinoma with EGFR germline mutations.

BACKGROUND: Germline mutations driving lung cancer have been infrequently reported in literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLC. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become standard-of-care treatment for EGFR T790M-positive lung cancer. METHODS: We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the UT MD Anderson Cancer Center. Of the patients that underwent cfDNA analysis, germline mutations were identified by those with high variant allelic fraction (VAF) approximating 50%, followed by further confirmation on genetic testing. RESULTS: We identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), Caucasian (86.4%), have family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%). Among the 18 with advanced-stage NSCLC, 12 (66.7%) were treated with first-line osimertinib, demonstrating a median PFS of 16.9 months (95% CI; 6.3-NR). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), mPFS was 20.4 months (95% CI; 6.3-NR) and mOS was 82.0 months (95% CI; 28.4-NR). CONCLUSION: Based on our institutional cohort, NSCLC driven by EGFR germline mutations occur more frequently in non-smoking, Caucasian females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC.

Efficacy of immunotherapy in oncogene-driven non-small-cell lung cancer.

For advanced metastatic non-small-lung cancer, the landscape of actionable driver alterations is rapidly growing, with nine targetable oncogenes and seven approvals within the last 5 years. This accelerated drug development has expanded the reach of targeted therapies, and it may soon be that a majority of patients with lung adenocarcinoma will be eligible for a targeted therapy during their treatment course. With these emerging therapeutic options, it is important to understand the existing data on immune checkpoint inhibitors (ICIs), along with their efficacy and safety for each oncogene-driven lung cancer, to best guide the selection and sequencing of various therapeutic options. This article reviews the clinical data on ICIs for each of the driver oncogene defined lung cancer subtypes, including efficacy, both for ICI as monotherapy or in combination with chemotherapy or radiation; toxicities from ICI/targeted therapy in combination or in sequence; and potential strategies to enhance ICI efficacy in oncogene-driven non-small-cell lung cancers.

Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer.

The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, the past few years have seen a paradigm shift with the emergence of several novel or later-generation TKIs with improved CNS penetrance. Such agents have promising levels of activity against brain metastases, as demonstrated by data from preclinical and clinical studies. In this Review, we describe current preclinical and clinical evidence of the intracranial activity of TKIs targeting various oncogenic drivers in patients with NSCLC, with a focus on newer agents with enhanced CNS penetration, leptomeningeal disease and the need for intrathecal treatment options. We also discuss evolving assessment criteria and regulatory considerations for future clinical investigations.

A review of perioperative anemia: A modifiable and not so benign risk factor.

Anemia is a commonly encountered finding either during the preoperative assessment or during the postoperative management of the patient. Anemia often gets overlooked while more emphasis is paid to cardiovascular and pulmonary evaluation. Evidence, however, suggests that the presence of anemia in the perioperative period can predispose patients to other complications. Awareness of the consequences of anemia in the perioperative period can lead to better recognition and early management of this potentially modifiable risk factor. In this review, we focus on the effects of anemia on the cardiac, pulmonary, neurologic, cognitive, and functional status outcomes of patients. We also review management strategies that could be employed, depending on the available time and resources.

Impact of ß-blockers on survival outcomes in patients with unresectable hepatocellular carcinoma.

Background: ß-blockers (BBs) have shown promise in improving overall survival (OS) in patients with breast, ovarian, pancreatic and lung cancer. However, few studies have evaluated the impact of BBs on unresectable hepatocellular carcinoma (HCC). Methods: The authors compared clinical data and outcomes between unresectable HCC patients based on whether they were prescribed BBs. Results: There was significantly decreased disease progression in the BB group compared with the non-BB group (22.8 vs 28.0%; p < 0.05). No difference was seen in OS or progression-free survival between groups. Those specifically on selective BBs had improved OS (hazard ratio: 0.75; 95% CI: 0.61-0.94; p = 0.01) and progression-free survival (hazard ratio: 0.66; 95% CI: 0.45-0.96; p = 0.03) compared with non-BB patients. Conclusion: Although the authors' study did not demonstrate that BBs improve OS in HCC, it did show decreased disease progression among patients with HCC who were taking BBs compared with those who were not.

Advanced Hepatocellular Carcinoma in Adults Without Cirrhosis: A Single-Institution Retrospective Review.

Background: Although up to one in five cases of hepatocellular carcinoma (HCC) occurs in patients without cirrhosis, there is scarce literature characterizing non-cirrhotic HCC (NCHCC). Existing NCHCC research is primarily limited to surgical case series and there is a lack of data on unresectable NCHCC. Aim: The purpose of this retrospective review was to compare the characteristics of unresectable NCHCC and cirrhotic hepatocellular carcinoma (CHCC). Methods: A retrospective chart review of adult patients with unresectable HCC treated from 2007 to 2017 was performed at the University of Florida Shands Hospital. The data set was stratified into two cohorts: NCHCC and CHCC. Continuous variables were compared using Wilcoxon-Mann-Whitney tests and Kruskal-Wallis rank-sum tests. Categorical variables were compared using Pearson's Chi-squared tests and Fisher's exact tests. Overall survival was explored utilizing the Kaplan-Meier and log-rank method. Results: There were 1494 adult patients included in the final analysis, including 264 patients (17.7%) with NCHCC and 1230 patients (82.3%) with CHCC. Median age was 61.0 years old and median follow-up time was 30.2 months. NCHCC patients were older than CHCC patients (66.3 years vs 61.9 years; p < 0.0001). NHCC tumors were larger than CHCC tumors (7.92 ± 4.85 vs 4.38 ± 3.12 cm; p < 0.0001) and more likely to be associated with distant metastases (23.35% vs 15.91%; p = 0.0055). There was no difference in overall survival, with a median of 23.5 months in NCHCC and 22.4 months in CHCC (p = 0.9196). Conclusion: Our findings suggest that unresectable NCHCC and CHCC have unique characteristics but similar overall survival. To the best of our knowledge, this is the largest comparison of CHCC and NCHCC.

CD26/Dipeptidyl Peptidase IV and Its Multiple Biological Functions.

CD26/Dipeptidyl peptidase IV (DPPIV) is a cell surface glycoprotein with numerous roles including glucose metabolism, immunomodulation, and tumorigenesis. CD26/DPPIV is well recognized in diabetes, with DPPIV inhibitors being a class of oral hypoglycemic drugs called gliptins that are commonly used to treat type two diabetes mellitus. Recent work also indicated a potential role for CD26 in infectious diseases, including COVID-19, and immune-mediated disorders such as rheumatoid arthritis, inflammatory bowel disease, and graft-versus-host disease. In cancer, CD26/DPPIV expression has been characterized in numerous tumors such as hematologic malignancies, malignant pleural mesothelioma (MPM), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), gastrointestinal stromal tumor (GIST), and prostate, lung, colorectal, and ovarian (PLCO) cancer. Hence, CD26 has been frequently studied as a tumor biomarker and therapeutic target. CD26/DPPIV-targeted therapies have been evaluated in various cancers, including the use of anti-CD26 monoclonal antibodies as anticancer treatment in selected neoplasms. This review highlights our current understanding of the role of CD26 in cancer, diabetes, immune-mediated diseases, and infectious diseases. Enhanced understanding of CD26 biology and function may lead to novel therapeutic approaches in multiple human diseases.

Anti-NMDAR encephalitis presenting after immature teratoma resection.

This is a case of a young woman who developed neurological and psychiatric symptoms 3 days after resection of an immature teratoma. She was diagnosed with anti-NMDA receptor encephalitis via positive serum antibody titres, which was later confirmed with cerebrospinal fluid antibody titres. Given her cancer diagnosis, she underwent treatment with bleomycin, etoposide and cisplatin chemotherapy in addition to 5 days of high-dose steroids (1 g of intravenous methylprednisolone) for the encephalitis. This treatment regimen led to significant clinical improvement 3 weeks after completion of one cycle of chemotherapy.

Reduction of immunosuppression for post-transplant lymphoproliferative disorder (PTLD): a single-center experience of allograft survival outcomes.

Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication of hematopoietic stem cell transplant and solid organ transplant. While reduction in immunosuppression (RIS) is the first-line treatment for PTLD, outcomes of allograft function as a result of RIS remain understudied. In this retrospective study, we examine rates of allograft rejection and graft failure after RIS in 141 patients diagnosed with PTLD at the University of Florida. Compared to prior literature demonstrating around 32-40% rate of allograft rejection as result of RIS, our institutional analysis revealed a much lower treatment-related allograft rejection rate of 18.4%. Out of the patients who experienced acute allograft rejection, 23.1% ultimately progressed to allograft failure. Interestingly, acute allograft rejection episodes during PTLD treatment were not statistically found to impact overall survival. RIS remains an overall beneficial treatment modality of PTLD due to its low allograft rejection rate relative to treatment rate.

A Multi-Center Retrospective Analysis Examining the Effect of Dipeptidyl Peptidase-4 Inhibitors on Progression-Free Survival in Patients With Prostate Cancer.

Background Cluster of differentiation 26/dipeptidyl peptidase-4 (DPP4) is a cell surface glycoprotein with multifaceted roles, including immune regulation, glucose metabolism, and tumorigenesis. Recent literature has identified DPP4 inhibitors to improve survival in diabetic patients with prostate cancer. DPP4 inhibitors have been proposed to play a role in prostate cancer, as DPP4 is found at higher levels in malignant prostate tissue compared to benign and correlates with PSA levels and cancer stage. In this multi-center retrospective study, we aim to define the effects of DPP4 inhibitors on progression-free survival (PFS) in diabetic patients with advanced-stage prostate cancer. Methodology We performed a retrospective analysis of 161 patients with diabetes and advanced-stage (III or IV) prostate cancer at the University of Florida Health Cancer Center and Moffitt Cancer Center. Our cohort included 120 patients on metformin (control group) and 41 on a DPP4 inhibitor (study group). Results No significant difference in progression of prostate cancer was identified between those on DPP4 inhibitors versus metformin (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.64-1.61; p = 0.955). Median time to progression was 3.5 years (range: 2.4-4.6 years). Conclusions Despite prior literature indicating survival benefit of DPP4 inhibitors in prostate cancer, our study did not identify a statistically significant improvement of PFS in diabetic patients with advanced prostate cancer. Additional analysis with larger sample sizes and prospective investigation with study of tumor microenvironment are needed to evaluate clinical impact and potential survival benefit of DPP4 inhibitors in prostate cancer.

A rare case of synovial sarcoma presenting as abdominal pain.

Abdominal pain can arise from numerous sources, including those extra-abdominal. It is important to obtain additional imaging in the setting of clinical suspicion for malignancy.

A Single-center Retrospective Analysis of the Effect of Radium-223 (Xofigo) on Pancytopenia in Patients with Metastatic Castration-resistant Prostate Cancer.

Introduction Radium-223 (Xofigo, Bayer Pharmaceuticals Inc., Whippany, NJ) has been shown to increase overall survival in patients with metastatic castration-resistant prostate cancer (mCRPC), via the phase 3 ALpharadin in SYMPtomatic Prostate CAncer (ASLYMPCA) study. Hematologic side effects of radium-223 included all-grade anemia in 31% of the patients, thrombocytopenia in 12%, and neutropenia in 5%, and persistent pancytopenia noted in 2%. However, the incidence seen in our institutional clinical practice is higher than that reported in the literature. Methods A retrospective analysis was performed by analyzing patients with mCRPC who received Xofigo at the University of Florida Health Shands Hospital (UF Health Shands) in a three-year span. Data collected included complete blood count (CBC), ECOG (Eastern Cooperative Oncology Group) functional status, kidney and liver function, evidence of bony disease on imaging, prior chemotherapy regimens, total radiation dose, and prostate-specific antigen (PSA).  Results Twenty-three patients received Xofigo at UF Health, and one was lost to follow-up. Sixteen patients (73%) completed the full course (six doses) of Xofigo, while six did not. Ten patients (45%) developed pancytopenia, with two recovering counts within eight months while the other eight had persistent cytopenias (six of which were transfusion-dependent). Older age and higher ECOG score correlated with increased risk of pancytopenia. In addition, a higher percentage of patients who received prior radiation therapy were more likely to develop pancytopenia (90% vs 75%). Conclusions  We found a higher rate of Xofigo-induced pancytopenia in our patient population than the 2% reported in the literature, albeit with a limited sample size, This may influence clinical decision making in the treatment of mCRPC, as pancytopenia may preclude patients from other survival-prolonging therapies. Factors such as age, functional status, and prior radiation therapy have to be considered prior to Xofigo treatment.

The Impact of Epidemiological Factors and Treatment Interventions on Survival in Patients With Signet Ring Cell Carcinoma of the Pancreas.

OBJECTIVES: Primary pancreatic signet ring cell carcinoma (SRCC) is a rare histologic variant of pancreatic carcinoma. A population-based analysis of pancreatic SRCC was performed to determine the predictive effects of epidemiological factors and treatment interventions on overall survival (OS) and disease-specific survival (DSS). MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results registry was searched for pancreatic SRCC cases diagnosed between January 1, 1973 and December 31, 2013. Statistical analysis was performed using the Fisher exact test, χ(2) analysis, Kaplan-Meier method, log-rank test, and Cox proportional hazards regression. RESULTS: The mean age among 497 patients was 66.6 years (SD, 11.9). Most patients were white (82.7%) and male (54.5%). The 1-, 2-, and 5-year OS rates were 17%, 9%, and 4%, respectively, while the corresponding 1-, 2-, and 5-year rates for DSS were 18%, 10%, and 5%, respectively. On univariable analysis; age, site, grade, stage, and treatment were predictive of OS and DSS (P<0.05). On multivariable analysis; radiation improved OS and DSS (adjusted hazard ratio [aHR], 0.592 and 0.589, respectively), pancreatectomy improved OS and DSS (aHR, 0.360 and 0.355, respectively), and combination therapy improved OS and DSS (aHR, 0.295 and 0.286, respectively). Age, site, and stage were also independent predictors of OS and DSS. Subgroup analysis demonstrated treatment to be an independent predictor of OS and DSS in localized/regional disease, in distant disease, and in patients diagnosed between 2000 and 2013. CONCLUSIONS: Age, site, stage, and treatment independently predict OS and DSS in pancreatic SRCC.

Increased energy intake and a shift towards high-fat, non-staple high-carbohydrate foods amongst China's older adults, 1991-2009.

OBJECTIVE: We examined trends from 1991-2009 in total energy intake and food group intake, and examine whether shifts varied by age or generation. DESIGN: Longitudinal time series (1991, 1993, 1997, 2000, 2004, 2006, 2009). SETTING: Nine provinces in China. PARTICIPANTS: Older Chinese aged ≥60 years (n=5,068) from the China Health and Nutrition Survey from 1991-2009. METHODS: Using three 24-hour recalls and a household food inventory collected over three consecutive days, the top twenty food group contributors to total energy intake from 1991-2009 were identified, and the mean kilocalorie (kcal) difference between 1991 and 2009 for each food group was ranked. The top twenty food group contributors to total energy intake from 1991-2009 were identified, and the mean kilocalorie (kcal) difference between 1991 and 2009 for each food group was ranked. Linear regression was used to examine changes in mean calorie intake of food groups between 1991 and 2009, adjusting for age, sex, and region. In addition, we examined changes in the mean kcal per capita intake to examine shifts by age group and generation. RESULTS: Mean total energy intake increased significantly among older Chinese adults from 1379 total kilocalories in 1991 to 1463 kilocalories in 2009 (p< 0.001). Most food groups showed a significant increase in intake from 1991 to 2009, with plant oil, wheat buns, and wheat noodles showing the greatest increase. At the same age, more recent generations had more energy intake than earlier generations. An aging effect was observed, with energy intake decreasing with age, although more recent generations showed a smaller decrease in energy intake with aging. CONCLUSION: Older Chinese adults in recent generations show an increase in total calorie intake compared to older Chinese of earlier generations, paired with a less significant decrease in calorie intake as they age. Increased consumption of high-fat, non-staple high-carbohydrate foods such as plant oil and wheat buns suggests that diet quality of older Chinese adults is becoming less healthful in recent years.